title: Discovery of novel small-molecule inhibitors of BRD4 using structure-based virtual screening.
abstract: Bromodomains (BRDs) are epigenetic readers that recognize acetylated-lysine (KAc) on proteins and are implicated in a number of diseases. We describe a virtual screening approach to identify BRD inhibitors. Key elements of this approach are the extensive design and use of substructure queries to compile a set of commercially available compounds featuring novel putative KAc mimetics and docking this set for final compound selection. We describe the validation of this approach by applying it to the first BRD of BRD4. The selection and testing of 143 compounds lead to the discovery of six novel hits, including four unprecedented KAc mimetics. We solved the crystal structure of four hits, determined their binding mode, and improved their potency through synthesis and the purchase of derivatives. This work provides a validated virtual screening approach that is applicable to other BRDs and describes novel KAc mimetics that can be further explored to design more potent inhibitors.
authors.affiliation: Division of Cancer Therapeutics, Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research , 15 Cotswold Road, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Vidler
authors.forename: Panagis
authors.initials: P
authors.lastname: Filippakopoulos
authors.forename: Oleg
authors.initials: O
authors.lastname: Fedorov
authors.forename: Sarah
authors.initials: S
authors.lastname: Picaud
authors.forename: Sarah
authors.initials: S
authors.lastname: Martin
authors.forename: Michael
authors.initials: M
authors.lastname: Tomsett
authors.forename: Hannah
authors.initials: H
authors.lastname: Woodward
authors.forename: Nathan
authors.initials: N
authors.lastname: Brown
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Swen
authors.initials: S
authors.lastname: Hoelder
mesh_terms: D018797:Cell Cycle Proteins; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D054852:Small Molecule Libraries; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins